American women of African ancestry (AA) are affected with more aggressive breast cancers and at younger ages than women of European ancestry (EA). Increasing evidence indicates that subtypes of breast cancer have different etiologies, and there are suggestive epidemiologic data regarding the relation of body size and physical activity to incidence of breast cancer subtypes (e.g., positive association of waist-hip ratio with basal-like cancer). AA women are more often obese and sedentary than EA women, differences that could be contributing to the observed breast cancer disparities. We will assess associations of body size and physical activity with subtypes of breast cancer by pooling data and DNA samples from four large studies of breast cancer in AA women: the Black Women's Health Study, the Carolina Breast Cancer Study, the Women's Circle of Health Study, and the Multi-ethnic Cohort. We propose to assess measures of body size, including overall obesity, abdominal obesity, and body mass index at age 18, and measures of physical activity at different times during the lifespan, in relation to incidence of breast cancer subtypes, including ER- /PR-, five intrinsic subtypes, and early onset breast cancer. Based on study subjects'DNA, we will genotype SNPs in the insulin and IGF-1 pathways, assess their association with the subtypes of breast cancer, and then assess the joint effects of body size and physical activity with the genetic variants on risk of the subtypes. Hypotheses of particular interest are that high WHR is associated with increased incidence of ER- /PR- and basal-like cancer, high body mass index with decreased incidence of premenopausal luminal A cancer, and physical activity, particularly in early reproductive years, with decreased incidence of ER-/PR- and basal-like cancer. In cross project aims, we will assess the modifying effects of genetic variants associated with breast cancer in Project 2 in the steroid hormone pathway and Project 4 in the inflammation pathway on the associations of body size and physical activity with breast cancer subtypes. This study has excellent power to achieve the proposed aims. The study will add appreciably to understanding of the etiology of aggressive breast cancers. It is particularly important to establish the nature of the associations of body size and physical activity with risk of breast cancer because these factors are modifiable.